9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (azithromycin) is the first and still the only marketed 15-member semi-synthetic macrolide antibiotic from the group of azalides [The Merck Index, 12th Ed. (1996), p. 157 (946)].
Azithromycin is an azalide antibiotic characterized by high intracellular and tissue concentrations and a very long half life. It has a broad spectrum of antimicrobial activity that includes common respiratory pathogens causing typical and atypical community acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), laryngitis, phayringitis, sinusitis, acute otitis media (AOM) and other respiratory infections.
The synthesis of azithromycin is described in Belgian patent No. 892357 (see also U.S. Pat. No. 4,517,359). It has a well-known antibacterial spectrum (J. Antimicrob. Chemother., 1987, 19, 275), mode of action (Antimicrob. Ag. Chemother., 1987, 31, 1939) and pharmacology (J. Antimicrob. Chemother. 1993, 31, Suppl. E, 1-198).
Non-hygroscopic 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate was prepared as early as the mid-1980's by neutralization of an acidic solution of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in an acetone-water mixture. Its crystal structure (single crystal) was evaluated upon recrystallization from ether, and was characterized by the orthorhombic space group P 212121. The unit cell parameters, namely crystal axes a=17.860 Å, b=16.889 Å and c=14.752 Å, and the angles between the crystal axes, α=β=γ=90°, were published in 1987 at the Meeting of Chemists of Croatia (Book of Abstracts, Meeting of Chemists of Croatia, Feb. 19-20, 1987, p. 29). Thereafter, its crystal structure and preparation were described in detail (J. Chem. Res. (S), 1988, 152, Ibid., miniprint 1988, 1239; received Jun. 4, 1987; Cambridge Crystallographic Data Base: GEGJAD).
Azithromycin dihydrate is customarily orally administered as a solid dosage form or oral suspension at a dose of 250 mg once daily for five consecutive days, or at a dose of 500 mg once daily for three consecutive days, or at a dose of 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 through 5.
It has been known that over the years many difficulties have arisen regarding patient compliance issues with a multi-day dosing regimen, because of forgetfulness as well as many other reasons. Pediatric patients in particular have difficulty in adhering to a multi day dosing scheme. For these reasons, it has been recognized that it would be desirable to administer an effective amount for treating respiratory infections in humans and other mammals with a single dose of azithromycin (see International Publication No. WO 03/018031). The population in third world countries, where respiratory infections are widespread, could benefit substantially from such single dosing regimen.
One difficulty or drawback observed during administration of a single dose of azithromycin dihydrate is that it involves gastrointestinal adverse events, sometimes referred to as side effects, that are incident to administration of oral azithromycin dihydrate dosages in excess of one gram. Reported adverse events include nausea, vomiting, abdominal pain and the like.
Extended release dosage compositions have been used in order to reduce the incidence and/or intensity of undesired effects following administration of a drug, by elimination of the peaks in drug concentration that often occur after administration of immediate release dosage forms (See Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th Edition, 1985, Chapter 1). Curatolo et al., in U.S. Pat. No. 6,068,859, describes the use of a controlled release dosage form of at least 1.0 gram to as high as 7.0 grams azithromycin in a single dose to treat respiratory infections. The dosage forms described in U.S. Pat. No. 6,068,859 are controlled release dosage forms, having specific delayed dissolution criteria (see FIG. 1 in U.S. Pat. No. 6,068,859).
It has now surprisingly been discovered that the adverse events that result from administration of, for example, single doses of a gram or more of azithromycin dihydrate can be overcome by orally administering to a patient in need of such treatment a single dose of an immediate release formulation containing a gram or more of a fast dissolving form of azithromycin, without the need for formulating an extended release dosage form.